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Mechanisms of Teleomere-Mediated Emphysema

端粒介导的肺气肿的机制

基本信息

批准号：
9081635
负责人：
Jonathan K. Alder
金额：
$ 12.62万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9081635
关键词：
Accounting Acute Age Animal Model Apoptosis Binding Biological Models Biology Bone Marrow Breeding Cell Aging Cell Cycle Arrest Cell Death Cell division Cells Cessation of life Characteristics Chromosomes Cigarette smoke-induced emphysema Complex Cyclin-Dependent Kinase Inhibitor DNA Damage DNA Sequence DNA Structure Data Defect Development Disease Elderly Environment Enzymes Epithelial Cells Failure Functional disorder Generations Genetic Goals Health Human In Vitro Individual Injury Investigation Knockout Mice Length Link Lung Lung diseases Mediating Mediator of activation protein Mentors Modeling Mus Mutation Pathogenesis Pathway interactions Peptide Hydrolases Phase Phenotype Population Predisposition Proteins Pulmonary Emphysema Research Risk Factors Role Smoking Stem cells TP53 gene Tandem Repeat Sequences Telomerase Telomerase RNA Component Telomere Shortening Telomere-Binding Proteins Testing Time Tissues Training United States Work abstracting age related base cell type cigarette smoke-induced cigarette smoking cytokine ds-DNA environmental tobacco smoke exposure genetic approach hTR RNA in vivo interest novel strategies novel therapeutic intervention prevent protein structure repaired response senescence telomere transcriptome

项目摘要

Project Summary/Abstract Emphysema causes an enormous health burden within the United States and worldwide. Smoking and advanced age are the biggest risk factors for its development, yet the genetic factors that contribute to emphysema susceptibility and its associated age-related onset are largely unknown. Telomeres are DNA and protein structures that protect the ends of chromosomes. Each time a cell divides, telomeres shorten and short telomeres activate a DNA damage response that triggers cell death or cell cycle arrest. Telomere lengths are heterogeneous in the population and shorten with age; but the link between telomeres and emphysema has not been explored in animal models. This proposal builds on exciting preliminary data we have generated that mice with short telomeres are more susceptible to cigarette smoke (CS) and develop emphysema. We have found that short telomeres limit the ability of lung epithelial cells to repair and recover after injury. This project will use mice with dysfunctional telomeres as a model system for studying emphysema biology and explore mechanisms that underlie its pathogenesis. In the first aim, we will genetically remove a key downstream regulator of cell cycle arrest following DNA damage and test if this rescues telomere-induced CS susceptibility. In the second aim, we will generate a new model to probe the consequences of telomere dysfunction in individual cell types within the lung to define the cellular basis for the emphysema susceptibility. Finally, in the third aim, we will examine the secreted proteins that mediate telomere-induced lung restructuring; this is the subject of the independent portion of this research. The proposed studies have potential to identify key pathways that contribute to emphysema pathogenesis. When identified, these mediators could potentially be targeted to treat or prevent emphysema. I have chosen an outstanding environment and group of mentors to complete the final years of my training. During the training period, I anticipate that the environment and additional training plan I have formulated will prepare me to establish an independent group that can make significant advances in translational lung research.

项目总结/摘要肺气肿在美国和世界范围内造成巨大的健康负担。吸烟和高龄是其发展的最大风险因素，然而，肺气肿的易感性及其与年龄相关的发病在很大程度上是未知的。端粒是DNA，保护染色体末端的蛋白质结构。细胞每次分裂时，端粒会缩短变短端粒激活DNA损伤反应，引发细胞死亡或细胞周期停滞。端粒长度是端粒在人群中具有异质性，并随着年龄的增长而缩短;但端粒与肺气肿之间的联系还没有在动物模型中探索过。这一建议建立在我们已经产生的令人兴奋的初步数据的基础上，端粒短的小鼠更容易受到香烟烟雾（CS）的影响并发展为肺气肿。我们有发现短端粒限制了肺上皮细胞在损伤后修复和恢复的能力。这个项目将使用端粒功能障碍的小鼠作为研究肺气肿生物学的模型系统，其发病机制的基础。在第一个目标中，我们将从基因上移除下游的一个关键点，调节DNA损伤后细胞周期停滞，并测试这是否挽救端粒诱导的CS易感性。在第二个目标中，我们将建立一个新的模型来探索端粒功能障碍在人类中的后果。肺内的单个细胞类型，以确定肺气肿易感性的细胞基础。最后在第三个目标，我们将研究介导端粒诱导的肺重构的分泌蛋白，这是这是本研究的独立部分。拟议的研究有可能确定关键的导致肺气肿发病的途径。一旦确定，这些介质可能是用于治疗或预防肺气肿。我选择了一个优秀的环境和一群导师，完成我最后几年的训练在培训期间，我预计环境和我制定的额外培训计划将使我准备建立一个独立的小组，转化肺研究的重大进展。